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The Current Trends and Future Prospects of Regenerative Medicine in Cardiovascular Diseases

Japan

INTRODUCTION

One of the recent advances, as well as attractive trends, in medical science is regenerative medicine because of its characteristic as translational research based on the most advanced basic sciences. The topics of regenerative medicine include gene therapy, cell transplantation, and tissue engineering, where therapeutic application is concerned. Regarding cell transplantation, stem cell research, both embryonic and mesenchymal, has been rapidly growing as the key to this new medical frontier. I shall give a brief review of currently practiced angiogenesis and cell-based cardiomyoplasty in advanced cardiovascular disease, and consider their roles in relation to surgical approaches.

ANGIOGENESIS

The targets of regenerative medicine have been mostly ischemic lesions such as peripheral arterial disease, ischemic heart disease, and heart failure. Currently, two modalities are practiced for angiogenesis: administration of angiogenic growth factors, and cell transplantation. Vascular endothelial growth factor, fibroblast growth factor, and hepatocyte growth factor (HGF) have been used. The source for cell transplantation is the mesenchymal or hematopoietic stem cell, mainly using bone marrow mononuclear cells (BMMNC) that contain endothelia progenitor (CD34+) cells.

Growth Factors.
In angiogenesis, gene therapy using adenovirus vectors with vascular endothelial growth factor and fibroblast growth factor have been conducted mainly in the United States for arterial obstruction of the lower extremities and also in the ischemic heart. Original work headed by Dr. Isner using vascular endothelial growth factor has shown very effective results and boosted this new strategy of angiogenesis.¹ However, because of the problems of viral vectors and regulatory issues, interest in gene delivery of growth factors has cooled as far as clinical trials are concerned. HGF has been intensively studied experimentally for its potential role in cell protection and other effects such as angiogenesis, anti-fibrotic action, and tissue regeneration. Using plasmid instead of viral vectors, an HGF gene therapy project named "Treat HGF", was introduced at Osaka University Hospital.² This is the first approved clinical trial in Japan of gene therapy for humans with a lifestyle-related disease, rather than a malignant or genetic disease. After completion of the phase I–II study, phase III of randomized trails has started. Gene therapy has potentially various ethical and medical drawbacks as far as current regulation is concerned, and it is now required that evidence be supported by randomized clinical trials. New vectors for gene therapy, novel techniques deleting the adverse effects of viral vectors, should be introduced, and one of such approaches may be the method of plasmid with cDNA, which all have potential benefits when applied as drug treatment.

Cell Transplantation.
BMMNC transplantation has been accepted as a strong modality of angiogenesis for limb-salvage in peripheral arterial disease after the breakthrough report in the Lancet by Tateishi-Yuyama and colleagues³ in 2002. In current practice, the number of treated patients has been increasing in many countries because of the inherent advantage of autotransplantation in avoiding the potential risks of rejection or infection. Importantly, this method is subject to little official regulation compared to gene therapy. For BMMNC transplantation, institutional review board approval is the only current requirement in Japan, and there is a growing number of practices in other Asian countries. During the next couple of years, there may be sufficient accumulation of evidence in support of the beneficial effects of BMMNC transplantation for angiogenesis to apply it clinically in peripheral arterial occlusive diseases. Interestingly, when the mechanism of BMMNC transplantation in ischemic tissue is considered, it has been speculated that such cells can secrete various cytokines or promote homing of endothelia progenitor cells. The application of BMMNC to the ischemic heart is still in the initial phase and it is premature to anticipate general acceptance. Currently, various protocols have been conducted worldwide using solo therapy or combining it with surgical revascularization. Methods of application include a transcatheter approach, intracoronary injection, or direct surgical injection. The evidence for beneficial effects of such treatment is still pending. However, we have to understand the difficulties of proving new angiogenesis or regenerated myocardium by even the most sophisticated angiographic studies or histology at the present time.

CELL-BASED CARDIOMYOPLASTY

For advanced heart failure, various new strategies are being attempted currently. Heart transplantation has been the standard approach in many countries, but in Asia, donor organ supply has been limited, and the use of assist devices restricted for economic reasons. Against this background, various left ventricular (LV) restorative surgical procedures have been proposed to treat advance heart failure, and practiced with mostly positive effects on symptomatic improvement. However, the survival rate appears to be limited in various LV-plasty techniques combined with revascularization. Recently, assist devices have been applied more often to end-stage heart failure, mainly as a bridge to transplantation, but there are increasing experiences of bridging to recovery using a left ventricular assist system (LVAS). So far, we have experienced a rather high incidence of recovery in patients with dilated cardiomyopathy who required long-term support with an LVAS, mainly with an implantable LVAS.⁴ Those with less myocardial fibrotic changes and shorter prior heart failure duration appear to be good candidates for bridging to recovery. However, simple unloading with or without pharmacological therapy under LVAS support may be of limited benefit to those with very advanced heart failure or ischemic cardiomyopathy.

The skeletal myoblast (SMB), rather than the cardiac myocyte, has provided a promising strategy for cell transplantation in the heart in which mechanical dysfunction is prominent with ventricular remodeling after myocardial infarction. Menasche and colleagues⁵ in Paris conducted an outstanding study in humans with an initial trial in 10 patients. Now it is reported that over 150 patients have received SMB transplantation in various institutions. In spite of the positive effects of restoring LV function, there has been criticism related to the risk of ventricular arrhythmia. Also, there has been no evidence of differentiation of SMB into cardiac myocytes, although some experimental studies have demonstrated such changes in vitro. Combined treatment of BMMNC and SMB transplantation is now an interesting approach to the treatment of advanced heart failure. Experimentally, such a combination has provided better ventricular function compared to isolated cell transplantation in rat and canine infarction models. From such basic experimental studies, we have started a clinical trial of combined cell transplantation of SMB with autologous BMMNC in ischemic cardiomyopathy. As a pilot study to determine safety and benefit, the trial is combined with LVAS support for patients with advanced ischemic cardiomyopathy. The result may provide important information about the safety and efficacy of such cell-based cardiomyoplasty in the setting of a bridge to recovery.

SOCIAL INTERESTS IN EMBRYONIC STEM CELL RESEARCH

In research on embryonic stem (ES) cells, there are growing interests and movements worldwide to organize intensively to bring the research towards human application. Just recently in the United States, California State decided to promote stem cell research, raising a 3-billion dollar bond over the next decade (Proposition 71) and establishing the California Institute for Regenerative Medicine. This action has been followed in other places. Now in the US, the study of ES cells is anticipated as the next source of economic power like a Stem Cell Valley, considering the previous Silicon Valley story. In Asian countries, the scientific momentum towards future human application of ES cells is only beginning. In Japan, the government has just set guidelines for the "establishment of human ES cell lines and their usage". If it is possible to start cell transplantation in patients using currently running ES cell lines, success cannot be obtained without appropriate rejection control because of the allogenicity of such cells. If we really want to establish a solution using stem cells, a cloning technique using our own somatic cells for autotransplantation seems mandatory.

SUMMARY

For the purpose of angiogenesis, cell transplantation of autologous bone marrow mononuclear cells, which may act as endothelia progenitor cells, has been rapidly growing because of the benefits of autotransplantation. For advanced heart failure, various strategies, surgical and regenerative, have been proposed. Cell transplantation using skeletal myoblasts has also been started for treatment of heart failure, as sole therapy or combined with surgical approaches including LVAS support. These enthusiastic trends using regenerative strategies in the cardiovascular field should be watched and performed carefully with consideration of their roles balanced against the achievements brought about by standard surgical approaches. Such new medical advances should be conducted in close collaboration with cardiovascular surgeons and innovative surgical approaches.

REFERENCES

1. Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996;348:370–4.[Medline]

2. Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J, et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 2004;44:203–9.[Abstract/Free Full Text]

3. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002;360:427–35.[Medline]

4. Matsuda H, Matsumiya G. Current status of left ventricular assist devices: the role in bridge to heart transplantation and future perspectives. J Artif Organs 2003;6:157–61.[Medline]

5. Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Cell Cardiol 2003;41:1078–83.

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